Project 1, Epidemiology & Environment, will leverage existing resources from two large epidemiologic studies to address the potential contribution from several common household exposures to risk for an autism spectrum disorder (ASD), separately and in combination with certain genomic or epigenetic profiles. The two existing investigations are: the population-based case-control CHARGE (CWildhood Autism Risk from Genetics and Environment) Study, and MARBLES (/Warkers of Autism Risk in Babies?Learning Early Signs), a cohort study following pregnant women who previously delivered a child that developed autism to understand what influences the outcome of the younger sibling and to identify early markers of ASD. Chemical classes of interest for Project 1 are: polybrominated diphenyl ethers (PBDEs, used as flame retardants), their hydroxylated metabolites, perfluorinated compounds (PFCs, used as coatings on non-stick cookware, textiles, food packaging, etc.), and pyrethroid insecticides (used in sprays and foggers to control ants, cockroaches, flies and mosquitos, and on pets to control fleas). Chemical determinations made in Core C in various media (plasma, urine, breastmilk) will be supplemented by toxicokinetic modeling and exposures assessed by questionnaire and other data sources. These will be examined in relation to child's developmental status, i.e., ASD, developmental delay (DD), specific speech /language delay, and other trajectories, and for associations with markers of immune function generated in Project 3, and epigenetic markers from Project 2. Differential impact of the PBDEs, PFCs, and pyrethroids will be evaluated based on relevant genetic polymorphisms, CNVs, or measures of global DNA methylation, considering mechanistic pathways that link to these compounds. Finally, with the bio-informatics team at Pennsylvania State Univ, we will explore, in discovery-oriented mode, a wide array of exposures from biologic specimens, interviews, and medical records, along with the genetic and epigenetic data. RELEVANCE (See instructions): This project squarely addresses the critical question: What causes autism? As rates of ASD (autism spectrum disorder) continue to climb, the burden on our communities becomes a major public health concern. By identifying modifiable risk factors, this project lays the groundwork for the development of prevention strategies, and by identifying early markers, it also provides the foundation for effective interventions.